Neutrophils may pave the way for new-generation immunotherapy

Neutrophils play a crucial role in suppressing or promoting tumour growth. Gene-edited neutrophils with SMAD3 deletion enhance neutrophil-mediated antitumour activity in non-small-cell lung cancer (NSCLC), according to researchers from the Chinese University of Hong Kong (CUHK).

Immunotherapy has revolutionized the NSCLC treatment landscape and improved patients’ outcomes. “However, only a small population of NSCLC patients [30 percent] respond to immune checkpoint inhibitors [ICIs] — the most commonly used immunotherapy in lung cancer,” said Dr Herbert Loong of the Department of Clinical Oncology, CUHK. [N Engl J Med 2017;377:2500-2501; Nat Commun 2023;14:1794] “A better understanding of the tumour microenvironment [TME] is key to resolving the clinical dilemma.”

Neutrophils are dynamic and shaped by TME

Neutrophils are abundant in the lung cancer microenvironment and closely related to cancer cell growth and drug resistance. However, their role in cancer treatment has been vastly overlooked until recently. [Int J Mol Sci 2020;21:7820; Nat Commun 2023;14:1794]

Neutrophils have dynamic phenotype and function, which could be shaped by the TME, such as N1 (anticancer) and N2 (protumour) states, but the mechanisms have remained unclear. The CUHK researchers used single-cell RNA sequencing (scRNA-seq) technology to investigate the dynamics and regulation of neutrophils in the lung cancer microenvironment.

“Unexpectedly, neutrophils are found to first exhibit the protumour N2 state in the lung cancer microenvironment, followed by the anticancer N1 state,” said Dr Jeff Chung of the Department of Anatomical and Cellular Pathology, CUHK.

SMAD3: Key regulator of N1/N2 polarization

“Notably, we found that the predominant phenotype in SMAD3-deficient mice is N1 neutrophils, and these mice showed significantly smaller tumour size vs controls [p<0.001] in the Lewis lung carcinoma [LLC] cell model,” Chung continued.

Based on this finding, the researchers hypothesized that SMAD3 may be the regulator of neutrophil N1/N2 polarization, which could be a therapeutic target for NSCLC.

To validate the hypothesis, the researchers used gene-editing technology to delete SMAD3 in neutrophils. Results showed that SMAD3 deletion significantly increased N1 neutrophils (p<0.001 vs controls) and thereby reduced tumour growth (p<0.001 vs controls) in mouse models.

Gene-edited neutrophils: Novel immunotherapy

“[Gene-edited neutrophils with SMAD3 deletion] effectively inhibited human lung carcinoma in vitro and in vivo, highlighting a possibility of developing neutrophils into a novel immunotherapy for lung cancer,” said Professor Ka-Fai To of the Department of Anatomical and Cellular Pathology, CUHK.

“Unlike current T cell–based immunotherapy, which utilizes adaptive immunity, neutrophils are innate immune cells that will not cause rejection even after allotransplantation,” pointed out Loong. As the most plentiful type of white blood cells, neutrophils can be easily harvested. “By overcoming therapeutic barriers of current immunotherapy, neutrophil-based immunotherapy is believed to benefit more patients,” commented Professor Patrick Tang of the Department of Anatomical and Cellular Pathology, CUHK. [Mol Cancer Ther 2021;20:961-974; Nat Commun 2023;14:1794]

“Importantly, our study led to the first patented invention using gene engineering to mass-produce anticancer neutrophils from human blood,” added To. Looking forward, the researchers hope to further transform gene-edited neutrophils into new-generation immunotherapy for lung cancer and other solid cancers in clinical practice.